The objective of the proposed research is to define the time course and extent of development of tolerance to certain respiratory and circulatory effects of methadone during prolonged administration of the drug. Studies will be done on former heroin addicts who are enrolled in a methadone maintenance program, and on goats. The human subjects will be selected to represent varying durations of methadone maintenance as well as varying daily dosages of the drug. All studies will be done before and 90 minutes after intake of the daily drug dose in order to assess both the acute and continual effects of methadone. In the human subject, the following elements of respiratory and circulatory control will be tested: 1) chemical control of breathing-ventilatory responses to CO2 and hypoxia; 2) neuro-mechanical control of breathing -ventilatory responses to mechanical loading and the effects of lung volume on breath-holding time; 3) ventilatory and circulatory (blood pressure and heart rate) responses to exercise; 4) circulatory responses to rapid positional change; 5) circulatory responses to the Valsalva maneuver. Studies on unanesthetized goats will involve measurement of blood pressure in the systemic and pulmonary circulations as well as cardiac output before and after methadone administration to addicted and non-addicted animals. In addition, the effects of certain perturbations of the circulation (acute hypovolemia and hypoxemia) will be assessed in relation to methadone intake. BIBLIOGRAPHIC REFERENCE: Effects of Morphine on the Ventilatory Response to Exercise. T.V. Santiago, J. Johnson and N.H. Edelman, Clin. Res. 23(3):351A, 1975.